The structure of the active site of human carbonic anhydrase II (HCAII) with iodide bound. There are four binding sites: I-1 and I-2 form inner- and outer-sphere ion pairs with the Zn2+ cofactor; I-3 binds to the interface of the hydrophobic and hydrophilic walls; and I-4 associates with a hydrophobic declivity near the mouth of the binding pocket.

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Figure 3.

The structure of immunoglobulin G, the most abundant example of a bivalent protein in mammalian biology

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Figure 4.

Crystal contacts between the molecules of human carbonic anhydrase II

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Whitesides Group Research

Biophysics

Molecular recognition—the non-covalent association of one molecule with another—is centrally important to biology. Non-covalent association guides the folding of proteins, the translation of DNA, the catalytic transformation of cellular metabolites, and the propagation of information throughout the cell (and between cells). The fundamental molecular driving forces involved in interactions between molecules have been enumerated (ionic, electrostatic, hydrophobic, etc.), but are not well understood. Building a fundamental understanding of these interactions will facilitate the rational design of biologically active molecules—from antibodies to ligands, which could serve as drug leads—, and enable the engineering of novel biologically-inspired, protein-based materials.

Our group studies molecular recognition in the contexts of protein-ligand interactions, protein crystallization, and multivalent receptor-ligand association. We integrate tools of calorimetry and thermodynamic analysis, protein crystallography and structural analysis, capillary electrophoresis, and molecular dynamics simulations with the goal of building structure-function relationships that will help us to understand the molecular-level origins that guide affinity and specificity in biomolecular association. We are particularly interested in the role water in hydrophobic interactions (1–4) and ionic interactions (5) (particularly those involving protein concavities), the relationship between protein surface chemistry and the interactions among proteins in their crystals, and the role of bivalency in biology and especially in the immune system (6, 7).